Cancer is a name given to a group of more than 100 diseases which have in common the disorganized growth of cells that invade tissues and organs, and which may spread to other regions of the body, what is known as metastasis.
Different types of cancers correspond to the various types of body cells. For instance, there are several types of skin cancer, as the skin is formed by more than one type of cell. If the cancer starts in the epithelial tissues, such as skin or a mucosa, it is called carcinoma. If it starts in the conjunctive tissues, such as bone, muscle or cartilage, it is called sarcoma. Other characteristics that distinguish one cancer from the other are the cell multiplication speed, and their ability to invade other tissues and organs, close or far from its origin.
The type-C protein kinases (PKC) comprise a group of protein kinases whose function and regulation are highly conservative. Kinases are also called phosphotransferases, and they phosphorilate serine and threonine residues from their substrates and regulate various cell activities, including gene expression, mitosis, cell movement, metabolism and programmed cell death (apoptosis). PKC are subject to phosphorilation before being activated, such a process taking place during its translocation of cytosol to the plasmatic membrane. Their activation and cytosol translocation to the plasmatic membrane occur in response to the transitory increase of diacylglycerol (DAG), or to exogenous agents, known as phorbol esters, typically present in plants.
The PKC family comprises 12 isoforms, divided into three subcategories: conventional (cPKC, calcium-dependent, and activated by DAG and phosphatidylserine), original (nPKC, calcium-independent, but activated by DAG and phosphatidylserine), and atypical (aPKC, calcium-independent, and activated by phosphatidylserine, but not by DAG). Within a single cell, the isoforms present differences in their distribution, before and after the translocation to the cellular membrane, and the literature suggests that the function of each isoform associated to a certain cell may be conferred by differences in the subcellular location of the PKC in the eitoplasmatic compartments of membrane and nuclear.
In recent years several studies have shown a relation between the disordered activation of PKC and the development of pathological processes, including rheumatoid arthritis, multiple sclerosis, colitis and different types of cancer. The hypothesis about PKC involvement in cancer has received much attention lately, based specially on the findings that those enzymes are the substrate for natural promoters of tumors, the phorbol esters. The increased or reduced activation of the serine-threonine protein kinases, including PKC, or of the transcription factors modulated by them, may result in the disorganized growth of cells, inducing the cancer process. In that sense, many studies have shown that after the activation of the PKC there occurs an increase in the phosphorilation of transcription factors, among them the nuclear factor Kappa B (NF-κB) and the activator protein 1 (AP-1), which, by their turn, modulate the expression of several proteins important for the progression of tumors, including ciclooxigenase-2 (COX-2). In this way, the activation or blockage of such intracellular path ways, natural compounds can interfere in the growth and proliferation of abnormal cells.
Phorbol esters are derived from tetracyclic diterpenes and seem to be restricted to the Euphorbiaceae and Thymelaceae plant families. Such compounds are frequently studied due to their particular tumor-promoting inducement and pro-inflammatory actions. The molecular mechanisms that regulate the tumor-promoting inducement of phorbol esters are different from the mechanisms that trigger the inflammatory activity. The tumor-promoting inducement seems to be associated with their ability to replace DAG in the activation of PKC, and also to their capacity to stimulate the synthesis of the RNA and DNA proteins, behaving as mitogenic agents and stimulating cellular growth. As to the pro-inflammatory activity, phorbol esters mobilize phospholipids, liberate arachidonic acid and cause prostaglandin secretion, leading to inflammatory response of the tissues. The topical application of phorbol esters, particularly TPA (tetradecanoylphorbol-13-acetate), have contributed to the understanding of molecular mechanisms concerned with inflammatory processes and cancer.
Some PKC inhibitors have been tested for the treatment of cancer in different phases of pre-clinical tests. One of them is the enzastaurin (LY317615), which shows an important activity when administered orally, and efficacy in different models of cancer, in vitro and in vivo (Journal of Investigative Dermatology (2006) 126, 1641-1647; Cancer Res (2005) 65:7462-7469; Mol Cancer Ther. (2006) 5:1783-1789).
The main problem in the treatment of anti-inflammatory diseases with NSAID (non-steroidal anti-inflammatory drugs) and steroidal drugs (corticoids) is the adverse effects caused by them and their non total efficacy. The most frequently reported side effects are: headache, stomachache, vomits, diarrhea, gastropathies such as stomach and duodenum ulcers. Corticoids may raise blood pressure, cause asteny and myopathy, peptic ulcers, petechies, erythema, acne, chronic headache, hirsutism, growth suppression in children (in long treatments), amenorrhea, cataract and glaucoma, appetite and weight gain, nausea. NSAIDs, the selective of COX-2, also can increase risks of serious thrombotic cardiovascular events, coronary thrombosis, and strokes.
As to the effective treatment of cancer, the difficulty is to establish the distinction between malignant and normal body cells. They share the same origin and are very similar, leading to the lack of recognition on the part of the immunologic system faced with a threat. Up to now, cancer has been treated by way of surgery, chemotherapy, radiotherapy and immunotherapy (monoclonal antibody therapy). The choice of treatment depends on the location, degree of the tumor and phase of the disease, as well as the general state of the patient. The complete removal of the tumor, with no damage to the rest of the organism is the main objective of the treatment, which can sometimes be obtained by surgery, but the propensity of the disease to invade adjacent tissues or to propagate to distant sites (metastasis) often limits its efficacy. The efficacy of chemotherapy is often limited by the toxicity to other cells of the organism, whereas radiotherapy may damage normal tissue. In immunotherapy cancer cells develop mechanisms to escape the immunologic response, a phenomenon known as treatment resistance.